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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5747-5756. Prepublished online as a Blood First Edition Paper on April 13, 2009; DOI 10.1182/blood-2008-10-186684. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-10-186684v1 113/23/5747    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhao, H. Articles by Persons, D. A. Search for Related Content PubMed PubMed Citation Articles by Zhao, H. Articles by Persons, D. A. Related Collections Hematopoiesis and Stem Cells Red Cells, Iron, and Erythropoiesis Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Amelioration of murine β-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both -globin and the MGMT drug-resistance gene Huifen Zhao1, Tamara I. Pestina1, Md Nasimuzzaman1, Perdeep Mehta2, Phillip W. Hargrove1, and Derek A. Persons1 1 Division of Experimental Hematology, Department of Hematology and 2 Bioinformatics Division, Department of Information Sciences, St Jude Children's Research Hospital, Memphis, TN Correction of murine models of β-thalassemia has been achieved through high-level globin lentiviral vector gene transfer into mouse hematopoietic stem cells (HSCs). However, transduction of human HSCs is less robust and may be inadequate to achieve therapeutic levels of genetically modified erythroid cells. We therefore developed a double gene lentiviral vector encoding both human -globin under the transcriptional control of erythroid regulatory elements and methylguanine methyltransferase (MGMT), driven by a constitutive cellular promoter. MGMT expression provides cellular resistance to alkylator drugs, which can be administered to kill residual untransduced, diseased HSCs, whereas transduced cells are protected. Mice transplanted with β-thalassemic HSCs transduced with a -globin/MGMT vector initially had subtherapeutic levels of red cells expressing -globin. To enrich -globin–expressing cells, transplanted mice were treated with the alkylator agent 1,3-bis-chloroethyl-1-nitrosourea. This resulted in significant increases in the number of -globin–expressing red cells and the amount of fetal hemoglobin, leading to resolution of anemia. Selection of transduced HSCs was also obtained when cells were drug-treated before transplantation. Mice that received these cells demonstrated reconstitution with therapeutic levels of -globin–expressing cells. These data suggest that MGMT-based drug selection holds promise as a modality to improve gene therapy for β-thalassemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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